tbuckley/cabot-search huggingface dataset:
Targeting Kindlin-2 in adipocytes increases bone mass through inhibiting FAS/PPARγ/FABP4 signaling in mice
Authors: Wanze Tang, Zhen Ding, Huanqing Gao, Qinnan Yan, Jingping Liu, Yingying Han, Xiaoting Hou, Zhengwei Liu, Litong Chen, Dazhi Yang, Guixing Ma, Huiling Cao
Journal: Acta Pharmaceutica Sinica B (2023)

Osteoporosis (OP) is a systemic skeletal disease that primarily affects the elderly population, which greatly increases the risk of fractures. Here we report that Kindlin-2 expression in adipose tissue increases during aging and high-fat diet fed and is accompanied by decreased bone mass. Kindlin-2 specific deletion (K2KO) controlled by Adipoq-Cre mice or adipose tissue-targeting AAV (AAV-Rec2-CasRx-sgK2) significantly increases bone mass. Mechanistically, Kindlin-2 promotes peroxisome proliferator-activated receptor gamma (PPARγ) activation and downstream fatty acid binding protein 4 (FABP4) expression through stabilizing fatty acid synthase (FAS), and increased FABP4 inhibits insulin expression and decreases bone mass. Kindlin-2 inhibition results in accelerated FAS degradation, decreased PPARγ activation and FABP4 expression, and therefore increased insulin expression and bone mass. Interestingly, we find that FABP4 is increased while insulin is decreased in serum of OP patients. Increased FABP4 expression through PPARγ activation by rosiglitazone reverses the high bone mass phenotype of K2KO mice. Inhibition of FAS by C75 phenocopies the high bone mass phenotype of K2KO mice. Collectively, our study establishes a novel Kindlin-2/FAS/PPARγ/FABP4/insulin axis in adipose tissue modulating bone mass and strongly indicates that FAS and Kindlin-2 are new potential targets and C75 or AAV-Rec2-CasRx-sgK2 treatment are potential strategies for OP treatment.
Increased TIM-3 and galectin-9 serum levels in patients with advanced systemic mastocytosis
Authors: Martina Konantz, Margaret Williams, Tamara Merkel, Antonia Reiss, Stefan Dirnhofer, Sara C. Meyer, Peter Valent, Tracy I. George, Alexandar Tzankov, Karin Hartmann
Journal: Journal of Allergy and Clinical Immunology (2023)

Background Systemic mastocytosis is characterized by expansion of clonal mast cells in various tissues. Several biomarkers with diagnostic and therapeutic potential have recently been characterized in mastocytosis, such as the serum marker tryptase and the immune checkpoint molecule PD-L1. Objective We aimed to investigate whether serum levels of other checkpoint molecules are altered in systemic mastocytosis and whether these proteins are expressed in mastocytosis infiltrates in the bone marrow. Methods Levels of different checkpoint molecules were analyzed in serum of patients with different categories of systemic mastocytosis and healthy controls and correlated to disease severity. Bone marrow biopsies from systemic mastocytosis patients were furthermore stained to confirm expression. Results Serum levels of TIM-3 and GAL-9 were increased in systemic mastocytosis, particularly in advanced subtypes, compared to healthy controls. TIM-3 and GAL-9 levels were also found to correlate with other biomarkers of systemic mastocytosis such as serum tryptase and KIT D816V variant allele frequency in the peripheral blood. Moreover, we observed expression of TIM-3 and GAL-9 in mastocytosis infiltrates in bone marrow. Conclusions Together, our results demonstrate for the first time that serum levels of TIM-3 and GAL-9 are increased in advanced systemic mastocytosis. Moreover, TIM-3 and GAL-9 are expressed in bone marrow infiltrates in mastocytosis. These findings provide a rationale for exploring TIM-3 and GAL-9 as diagnostic markers and eventually also therapeutic targets in systemic mastocytosis, particularly in advanced forms.
Restoring tumor immunogenicity with dendritic cell reprogramming
Authors: Olga Zimmermannova, Alexandra G. Ferreira, Ervin Ascic, Marta Velasco Santiago, Ilia Kurochkin, Morten Hansen, Özcan Met, Inês Caiado, Ilja E. Shapiro, Justine Michaux, Marion Humbert, Diego Soto-Cabrera, Hreinn Benonisson, Rita Silvério-Alves, David Gomez-Jimenez, Carina Bernardo, Monika Bauden, Roland Andersson, Mattias Höglund, Kenichi Miharada, Yukio Nakamura, Stephanie Hugues, Lennart Greiff, Malin Lindstedt, Fábio F. Rosa, Cristiana F. Pires, Michal Bassani-Sternberg, Inge Marie Svane, Carlos-Filipe Pereira
Journal: Science Immunology (2023)

Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8+ T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross-presented antigens to naïve CD8+ T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.
The interplay between the DNA damage response and ectonucleotidases modulates tumor response to therapy
Authors: John Stagg, Encouse Golden, Erik Wennerberg, Sandra Demaria
Journal: Science Immunology (2023)

The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the ectonucleotidase CD73. The pro-inflammatory nucleotides adenosine triphosphate, nicotinamide adenine dinucleotide, and cyclic guanosine -monophosphate-AMP (cGAMP), which are produced in the tumor microenvironment (TME) during therapy-induced immunogenic cell death and activation of innate immune signaling, can be converted into AMP by ectonucleotidases CD39, CD38, and CD203a/ENPP1. Thus, ectonucleotidases shape the TME by converting immune-activating signals into an immunosuppressive one. Ectonucleotidases also hinder the ability of therapies including radiation therapy, which enhance the release of pro-inflammatory nucleotides in the extracellular milieu, to induce immune-mediated tumor rejection. Here, we review the immunosuppressive effects of adenosine and the role of different ectonucleotidases in modulating antitumor immune responses. We discuss emerging opportunities to target adenosine generation and/or its ability to signal via adenosine receptors expressed by immune and cancer cells in the context of combination immunotherapy and radiotherapy.
3D chromatin reprogramming primes human memory T <sub>H</sub> 2 cells for rapid recall and pathogenic dysfunction
Authors: Anne Onrust-van Schoonhoven, Marjolein J.W. de Bruijn, Bernard Stikker, Rutger W.W. Brouwer, Gert-Jan Braunstahl, Wilfred F.J. van IJcken, Thomas Graf, Danny Huylebroeck, Rudi W. Hendriks, Grégoire Stik, Ralph Stadhouders
Journal: Science Immunology (2023)

Memory T cells provide long-lasting defense responses through their ability to rapidly reactivate, but how they efficiently "recall" an inflammatory transcriptional program remains unclear. Here, we show that human CD4+ memory T helper 2 (TH2) cells carry a chromatin landscape synergistically reprogrammed at both one-dimensional (1D) and 3D levels to accommodate recall responses, which is absent in naive T cells. In memory TH2 cells, recall genes were epigenetically primed through the maintenance of transcription-permissive chromatin at distal (super)enhancers organized in long-range 3D chromatin hubs. Precise transcriptional control of key recall genes occurred inside dedicated topologically associating domains ("memory TADs"), in which activation-associated promoter-enhancer interactions were preformed and exploited by AP-1 transcription factors to promote rapid transcriptional induction. Resting memory TH2 cells from patients with asthma showed premature activation of primed recall circuits, linking aberrant transcriptional control of recall responses to chronic inflammation. Together, our results implicate stable multiscale reprogramming of chromatin organization as a key mechanism underlying immunological memory and dysfunction in T cells.
Table of Contents
Authors: E Basch, I Tannock, G Bouche, D Goldstein, Y Goto, A Lichter, K Prabhash, P Ranganathan, L Saltz, G Sonke, G Strohbehn, R Von Moos, M Ratain, P Tarantino, G Viale, M Press, X Hu, F Penault-Llorca, A Bardia, A Batistatou, H Burstein, L Carey, J Cortes, C Denkert, V Diéras, W Jacot, A Koutras, A Lebeau, S Loibl, S Modi, M Mosele, E Provenzano, G Pruneri, J Reis-Filho, F Rojo, R Salgado, P Schmid, S Schnitt, S Tolaney, D Trapani, A Wolff, G Pentheroudakis, F André, G Curigliano
Journal: Annals of Oncology (2023)
Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging
Authors: A Bertolino, S Nawroz, V S Mattay, A S Barnett, J H Duyn, C T Moonen, J A Frank, G Tedeschi, D R Weinberger
Journal: American Journal of Psychiatry (1996)

Several single-voxel proton magnetic resonance spectroscopy (1H-MRS) studies of patients with schizophrenia have found evidence of reductions of N-acetyl-aspartate (NAA) concentrations in the temporal lobes. Multislice proton magnetic resonance spectroscopy imaging (1H-MRSI) permits simultaneous acquisition and mapping of NAA, choline-containing compounds (CHO), and creatine/phosphocreatine (CRE) signal intensities from multiple whole brain slices consisting of 1.4-ml single-volume elements. We have used 1H-MRSI to assess the regional specificity of previously reported changes of metabolite signal intensities in schizophrenia. Hippocampal volume was also measured to test the relationship between 1H-MRSI findings and tissue volume in this region.Ratios of areas under the metabolite peaks of the proton spectra were determined (i.e., NAA/CRE, NAA/CHO, CHO/CRE) for multiple cortical and subcortical regions in 10 inpatients with schizophrenia.Patients showed significant reductions of NAA/CRE and NAA/CHO bilaterally in the hippocampal region and in the dorsolateral prefrontal cortex. There were no significant changes in CHO/CRE or in NAA ratios in any other area sampled. No significant correlation was found between metabolite ratios in the hippocampal region and its volume.NAA-relative signal intensity reductions in schizophrenia appear to be remarkably localized, involving primarily the hippocampal region and the dorsolateral prefrontal cortex, two regions implicated prominently in the pathophysiology of this disorder.
CD71-mediated liposomal arsenic-nickel complex combined with all-trans retinoic acid for the efficacy of acute promyelocytic leukemia
Authors: Xiao Liu, Lili Zhang, Yueying Yang, Weiwei Yin, Yunhu Liu, Chunyi Luo, Ruizhe Zhang, Zhiguo Long, Yanyan Jiang, Bing Wang
Journal: Asian Journal of Pharmaceutical Sciences (2023)

Clinically, arsenic trioxide (ATO) was applied to the treatment of acute promyelocytic leukemia (APL) as a reliable and effective frontline drug. However, the administration regimen of AsⅢ was limited due to its fast clearance, short therapeutic window and toxicity as well. Based on CD71 overexpressed on APL cells, in present study, a transferrin (Tf)-modified liposome (LP) was established firstly to encapsulate AsⅢ in arsenic-nickel complex by nickel acetate gradient method. The AsⅢ-loaded liposomes (AsLP) exhibited the feature of acid-sensitive release in vitro. Tf-modified AsLP (Tf-AsLP) were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release AsⅢ which stimulated reactive oxygen species level and caspase-3 activity. Tf-AsLP prolonged half-life of AsⅢ in blood circulation, lowered systemic toxicity, and promoted apoptosis and induced cell differentiation at lesion site in vivo. Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect, accordingly, a Tf-modified RA liposome (Tf-RALP) was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy. As expected, the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model. Furthermore, APL orthotopic NOD/SCID mice model was established by 60CO irradiation and HL-60 cells intravenously injection. The effect of co-administration (Tf-AsLP + Tf-RALP) was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells' apoptosis and differentiation in peripheral blood and bone marrow. Collectively, Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug. Moreover, Tf-AsLP combined with Tf-RALP could achieve better efficacy. Thus, transferrin-modified AsⅢ liposome would be a novel clinical strategy to improve patient compliance, with promising translation prospects.
Prolonged vs short-term infusion of β-lactam antibiotics for the treatment of febrile neutropenia: A systematic review and meta-analysis
Authors: J. Laporte-Amargos, M. Ulldemolins, M. Puig-Asensio, C. Tebé, S. Castro, J. Carratalà, C. Gudiol
Journal: Journal of Infection (2023)

The optimisation of the use of β-lactam antibiotics (BLA) via prolonged infusions in life-threatening complications such as febrile neutropenia (FN) is still controversial. This systematic review and meta-analysis aim to evaluate the efficacy of this strategy in onco-haematological patients with FN.
Phytoestrogen-derived multifunctional ligands for targeted therapy of breast cancer
Authors: Ying Zhang, Hao Pan, Changxiang Yu, Rui Liu, Bin Xing, Bei Jia, Jiachen He, Xintao Jia, Xiaojiao Feng, Qingqing Zhang, Wenli Dang, Zheming Hu, Xiuping Deng, Pan Guo, Zhidong Liu, Weisan Pan
Journal: Asian Journal of Pharmaceutical Sciences (2023)

Nano-targeted delivery systems have been widely used for breast tumor drug delivery. Estrogen receptors are considered to be significant drug delivery target receptors due to their overexpression in a variety of tumor cells. However, targeted ligands have a significant impact on the safety and effectiveness of active delivery systems, limiting the clinical transformation of nanoparticles. Phytoestrogens have shown good biosafety characteristics and some affinity with the estrogen receptor. In the present study, molecular docking was used to select tanshinone IIA (Tan IIA) among phytoestrogens as a target ligand to be used in nanodelivery systems with some modifications. Modified Tan IIA (Tan-NH2) showed a good biosafety profile and demonstrated tumor-targeting, anti-tumor and anti-tumor metastasis effects. Moreover, the ligand was utilized with the anti-tumor drug Dox-loaded mesoporous silica nanoparticles via chemical modification to generate a nanocomposite Tan-Dox-MSN. Tan-Dox-MSN had a uniform particle size, good dispersibility and high drug loading capacity. Validation experiments in vivo and in vitro showed that it also had a better targeting ability, anti-tumor effect and lower toxicity in normal organs. These results supported the idea that phytoestrogens with high affinity for the estrogen receptor could improve the therapeutic efficacy of nano-targeted delivery systems in breast tumors.
Site-specific development and progressive maturation of human tissue-resident memory T cells over infancy and childhood
Authors: Thomas J. Connors, Rei Matsumoto, Shivali Verma, Peter A. Szabo, Rebecca Guyer, Joshua Gray, Zicheng Wang, Puspa Thapa, Pranay Dogra, Maya M.L. Poon, Ksenia Rybkina, Marissa C. Bradley, Emma Idzikowski, James McNichols, Masaru Kubota, Kalpana Pethe, Yufeng Shen, Mark A. Atkinson, Maigan Brusko, Todd M. Brusko, Andrew J. Yates, Peter A. Sims, Donna L. Farber
Journal: Immunity (2023)
Single-cell dissection of Merkel cell carcinoma heterogeneity unveils transcriptomic plasticity and therapeutic vulnerabilities
Authors: Bhaba K. Das, Aarthi Kannan, Graham J. Velasco, Mikaela D. Kunika, Nils Lambrecht, Quy Nguyen, Haibo Zhao, Jie Wu, Ling Gao
Journal: Cell Reports Medicine (2023)

Merkel cell carcinoma (MCC), a rare but aggressive skin cancer, remains a challenge in the era of precision medicine. Immune checkpoint inhibitors (ICIs), the only approved therapy for advanced MCC, are impeded by high primary and acquired resistance. Hence, we dissect transcriptomic heterogeneity at single-cell resolution in a panel of patient tumors, revealing phenotypic plasticity in a subset of treatment-naive MCC. The tumor cells in a "mesenchymal-like" state are endowed with an inflamed phenotype that portends a better ICI response. This observation is also validated in the largest whole transcriptomic dataset available from MCC patient tumors. In contrast, ICI-resistant tumors predominantly express neuroepithelial markers in a well-differentiated state with "immune-cold" landscape. Importantly, a subtle shift to "mesenchymal-like" state reverts copanlisib resistance in primary MCC cells, highlighting potential strategies in patient stratification for therapeutics to harness tumor cell plasticity, augment treatment efficacy, and avert resistance.
Germinal center-dependent and -independent immune responses of tumor-infiltrating B cells in human cancers
Authors: Eve Playoust, Romain Remark, Eric Vivier, Pierre Milpied
Journal: Cellular and Molecular Immunology (2023)

B cells play essential roles in immunity, mainly through the production of high affinity plasma cells (PCs) and memory B (Bmem) cells. The affinity maturation and differentiation of B cells rely on the integration of B-cell receptor (BCR) intrinsic and extrinsic signals provided by antigen binding and the microenvironment, respectively. In recent years, tumor infiltrating B (TIL-B) cells and PCs (TIL-PCs) have been revealed as important players in antitumor responses in human cancers, but their interplay and dynamics remain largely unknown. In lymphoid organs, B-cell responses involve both germinal center (GC)-dependent and GC-independent pathways for Bmem cell and PC production. Affinity maturation of BCR repertoires occurs in GC reactions with specific spatiotemporal dynamics of signal integration by B cells. In general, the reactivation of high-affinity Bmem cells by antigens triggers GC-independent production of large numbers of PC without BCR rediversification. Understanding B-cell dynamics in immune responses requires the integration of multiple tools and readouts such as single-cell phenotyping and RNA-seq, in situ analyses, BCR repertoire analysis, BCR specificity and affinity assays, and functional tests. Here, we review how those tools have recently been applied to study TIL-B cells and TIL-PC in different types of solid tumors. We assessed the published evidence for different models of TIL-B-cell dynamics involving GC-dependent or GC-independent local responses and the resulting production of antigen-specific PCs. Altogether, we highlight the need for more integrative B-cell immunology studies to rationally investigate TIL-B cells as a leverage for antitumor therapies.
Corrigendum to Affordable oral proinsulin bioencapsulated in plant cells regulates blood sugar levels similar to natural insulin. Biomaterials 298, 122142, (2023)
Authors: Henry Daniell, Rahul Singh, Venkata Mangu, Smruti K. Nair, Geetanjali Wakade, Nataliya Balashova
Journal: Biomaterials (2023)
Corrigendum to A hypochlorite-activated strategy for realizing fluorescence turn-on, type I and type II ROS-combined photodynamic tumor ablation Biomaterials Volume 297, 122108, (2023)
Authors: Tonghui Huang, Heng Ji, Shirong Yan, Yifan Zuo, Jie Li, Jacky W.Y. Lam, Cuiping Han, Ben Zhong Tang
Journal: Biomaterials (2023)
Potential value of pre-planned imaging of bone disease in multiple myeloma
Authors: Michael T. Gundesen, Jon Thor Asmussen, Fredrik Schjesvold, Annette Juul Vangsted, Carsten Helleberg, Einar Haukås, Trine Silkjær, Elena Manuela Teodorescu, Bo Amdi Jensen, Tobias S. Slørdahl, Hareth Nahi, Anders Waage, Niels Abildgaard, Thomas Lund
Journal: Blood Cancer Journal (2023)
Anticancer effects of ikarugamycin and astemizole identified in a screen for stimulators of cellular immune responses
Authors: Shuai Zhang, Liwei Zhao, Mengfei Guo, Peng Liu, Sijing Li, Wei Xie, Ai-Ling Tian, Jonathan G Pol, Hui Chen, Hui Pan, Misha Mao, Yumei Li, Laurence Zitvogel, Yang Jin, Oliver Kepp, Guido Kroemer
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Most immunotherapies approved for clinical use rely on the use of recombinant proteins and cell-based approaches, rendering their manufacturing expensive and logistics onerous. The identification of novel small molecule immunotherapeutic agents might overcome such limitations. Method For immunopharmacological screening campaigns, we built an artificial miniature immune system in which dendritic cells (DCs) derived from immature precursors present MHC (major histocompatibility complex) class I-restricted antigen to a T-cell hybridoma that then secretes interleukin-2 (IL-2). Results The screening of three drug libraries relevant to known signaling pathways, FDA (Food and Drug Administration)-approved drugs and neuroendocrine factors yielded two major hits, astemizole and ikarugamycin. Mechanistically, ikarugamycin turned out to act on DCs to inhibit hexokinase 2, hence stimulating their antigen presenting potential. In contrast, astemizole acts as a histamine H1 receptor (H1R1) antagonist to activate T cells in a non-specific, DC-independent fashion. Astemizole induced the production of IL-2 and interferon-γ (IFN-γ) by CD4 + and CD8 + T cells both in vitro and in vivo. Both ikarugamycin and astemizole improved the anticancer activity of the immunogenic chemotherapeutic agent oxaliplatin in a T cell-dependent fashion. Of note, astemizole enhanced the CD8 + /Foxp3 + ratio in the tumor immune infiltrate as well as IFN-γ production by local CD8 + T lymphocytes. In patients with cancer, high H1R1 expression correlated with low infiltration by TH1 cells, as well as with signs of T-cell exhaustion. The combination of astemizole and oxaliplatin was able to cure the majority of mice bearing orthotopic non-small cell lung cancers (NSCLC), then inducing a state of protective long-term immune memory. The NSCLC-eradicating effect of astemizole plus oxaliplatin was lost on depletion of either CD4 + or CD8 + T cells, as well as on neutralization of IFN-γ. Conclusions These findings underscore the potential utility of this screening system for the identification of immunostimulatory drugs with anticancer effects.